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Effects of Phorbol Esters and Forskolin on Basal and Histamine‐induced Accumulation of Inositol Phosphates in Cultured Bovine Adrenal Chromaffin Cells
Author(s) -
Wan David C. C.,
Bunn Stephen J.,
Livett Bruce G.
Publication year - 1989
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1989.tb07418.x
Subject(s) - forskolin , histamine , inositol , inositol phosphate , phorbol , endocrinology , medicine , catecholamine , chemistry , inositol trisphosphate , protein kinase c , chromaffin cell , biology , stimulation , biochemistry , receptor , adrenal medulla , phosphorylation
The effect of phorbol esters and forskolin pretreat‐ment on basal and histamine‐induced accumulation of inositol phosphates and catecholamine release was Examined in cultures of bovine adrenal chromaffin cells. Histamine caused a dose‐dependent, Ca 2+ ‐dependent accumulation of total inositol phosphates with an EC 50 at ∼ 1 μMandjan eight‐ to 10‐fold increase at 100 μ M within 30 min of jincubation. Histamine (10 μ M ) also caused the release of cellular catecholamines amounting to some 2.8% of cellular stores released over a 20‐min period. Both the inositol phosphite and catecholamine responses were completely blocked by the H r antagonist mepyramine and were insensitive tojthe H 2 ‐antagonist cimetidine. Examination of the time course of accumulation of the individual inositol phosphatesj stimulated by histamine revealed an early and sustained rise| in inositol 1,4‐bisphosphate content but not inositol 1,4,5‐trikphosphate content at 1 min and the overall largest accumulation of inositol monophosphate after 30 min of stimulation. Pretreatment with the tumor‐promoting phorbol ester phorbol 12‐myristate 13‐acetate (PMA) resulted in a dose‐dependent, time‐dependent inhibition of histamine‐induced inositol phosphate formation and catecholamine secretion. In this inhibitory action, PMA exhibited high potency (IC 5o of ∼0.5 n M ), an effect not shared by the inactive phorbol ester 4‐a ‐phorbol 12,13‐didecanoate. Pretreatment with forskolin, on the other hand, only marginally inhibited the histamine‐induced inositol phospholipid metabolism and catecholamine secretion. These data suggest that protein kinase C activation in chromaffin cells may mediate a negative feedback control on inositol phospholipid metabolism.